One of every three cancers diagnosed in American males is of prostatic origin, making prostate cancer the most commonly diagnosed malignancy in males in the United States (Berges et al. Clin. Cancer Res. 1:473-480, 1995). The incidence of prostate cancer in the U.S. has not been decreased by changes in lifestyle; in fact, the incidence rate of clinical prostate cancer has increased steadily since the 1930's (Pinski et al. Cancer Res. 61:6372-6, 2001). Prostate cancer incidence increases with age more rapidly than any other type of cancer; less than 1% of prostate cancers are diagnosed in men less than 50 years of age (Furuya et al. Cancer Res. 54:6167-75, 1994). Thus, as the life expectancy of the male population increases over time, the incidence of clinical prostate cancer will also increase (Furuya et al. Cancer Res. 54:6167-75, 1994).
Currently there is no treatment that significantly prolongs survival in men with metastatic prostate cancer (Khan and Denmeade. Prostate 45:80-83, 2000). Medical castration with oral estrogen (androgen ablation) was the first effective systemic therapy for cancer, and remains the most generally useful prostate cancer therapy. Although androgen ablation therapy has a substantial palliative benefit, it has little impact on overall survival (Berges et al. Clin. Cancer Res. 1:473-480, 1995). This therapy eventually fails because the metastatic prostate cancer within an individual patient is heterogeneously composed of androgen-dependent and androgen-independent cancer cells (Christensen et al. Bioorg. Medicinal Chem. 7:1273-80, 1999). Following androgen ablation, androgen-dependent cells within these tumors stop proliferating and activate a cellular suicide pathway termed programmed cell death (PCD) or apoptosis. Because of the elimination of this subgroup of androgen-dependent cells, the majority of men with metastatic prostate cancers have a beneficial response to androgen-deprivation therapy. However, all patients eventually relapse to a state unresponsive to further anti-androgen therapy, no matter how completely given, due to the presence of androgen-independent prostate cancer cells within the metastatic sites. Unfortunately, the disease is uniformly fatal at this point because currently there is no therapy that effectively eliminates androgen-independent prostate cancer cells (Khan and Denmeade. Prostate 45:80-83, 2000).
Several alternative approaches to the treatment of prostate cancer have been proposed. One has been to develop methods to aggressively screen for local disease while it is still in the prostate and thus potentially treatable by definitive local therapy. Localized cancers are often moderately differentiated and smaller in volume. During the last several decades, there have been improvements to the surgical and radiotherapeutic management of localized prostate cancer. These improvements have culminated over the last several years in the death rate of prostate cancer decreasing for the first time in fifty years.
However, while this advance increased the cure rate, there are still a large number of men who are not cured by local therapies and eventually die from metastatic disease. This clinical reality has led to the development of non-hormonal treatments for metastatic prostate cancer. Standard anti-proliferative chemotherapeutic agents have not been successful as treatment for prostate cancer. These types of agents may be ineffective against androgen-independent prostatic cancers because these cancers have a remarkably low rate of proliferation when compared to other tumor types and many normal tissues such as skin, gastrointestinal tract and bone marrow. For example, the growth fraction in 117 metastatic sites of prostate cancer obtained from 11 androgen ablation failing patients at “warm” autopsy was 7.1±0.8%. (Pinski et al. Cancer Res. 61:6372-6, 2001). This low proliferative rate may explain the relative unresponsiveness of prostate cancer cells in humans to standard anti-proliferative chemotherapy, while highly proliferative androgen independent prostate cancer cell lines remain exquisitely sensitive to PCD induction in vitro.
Several strategies have been proposed for treatment of slowly-proliferating prostate cancers. One approach is to identify specific signaling pathways to which prostate cancer cells, during malignant transformation, acquire a unique dependence for survival. Once identified, small molecule or biological inhibitors of these pathways can be developed as therapeutics. An example of this approach is the use of small molecule or monoclonal antibody inhibitors of the Her2/neu or EGF receptor pathways. Another method is to inhibit a ubiquitous intracellular protein whose function is mandatory for survival of all cell types. This approach would overcome the problem of heterogeneity and “resistance” as all cancer cells within a tumor could be killed via this approach. However, the cytotoxicity would not be cell-type specific and administration of such a general toxin would be associated with significant systemic toxicity. Therefore, there is a need for a method for targeting cytotoxins directly to sites of prostate cancer.
Another strategy for treatment of slowly proliferating prostate cancers is to deliver. cytotoxins that kill cells not through induction of apoptosis following inhibition of critical signaling or metabolic pathways but rather through non-specific cytolysis via disruption of the plasma membrane. Many cytolytic toxins have been described (Lesieur et al. Mol. Membr. Biol. 14:45064, 1997). These cytolytic toxins are often of bacterial origin, and, in general, are beta-sheet proteins that oligomerize in the plasma membrane to produce well-characterized pores that, once formed, lead to rapid cytolytic cell death (Rossjohn et al. J. Struct. Biol. 121:92-100,1998). These toxins are also non-specific in their ability to kill cells, and therefore can not be administered as therapy without significant toxicity. Therefore, there is a need for agents to treat prostate cancer, which are predominantly cytotoxic to prostate cancer cells.